Hereditary hemochromatosis (HH) is a common disease characterized by excess iron deposition in the major organs of the body (Dadone, M. M. et al. AM. J. Clin. Pathol. 78:196-207 (1982); Edwards, C. Q. et al. N. Engl. J. Med. 18:1355-1362. (1988); McLaren, C. E., et al. Blood 86:2021-2027 (1995); Bothwell, T. H. et al., The metabolic and molecular basis of inherited disease (ed. C. R. Scriver, E. A.) 2237-2269 (McGraw-Hill, New York 1995); Bacon, B. R. et al., Hepatology, A textbook of liver disease (eds. Zakim, D. and Boyer, T. D.) 1439-1472 (W. B. Saunders, Philadelphia, 1996). A candidate gene for this disease, HFE, was identified by positional cloning (Feder, J. N., et al. Nature Genetics 13:399-408 (1996)). The gene, a novel member of the MHC class I family, was found to have a mutation, cysteine 282xe2x86x92tyrosine (C282Y), in 83% of patient chromosomes (Feder, J. N., et al. Nature Genetics 13:399-408 (1996)). This mutation eliminates the ability of HFE to associate with xcex22-microglobulin (xcex22m) and prevents cell-surface expression (Feder, J. N., et al., J. Biol. Chem. 272:14025-14028 (1997)). However, the relationship of this class I-like molecule to the regulation of iron metabolism has remained obscure.
Thus, an object of the instant invention is to provide a molecular basis for the relationship of HFE to iron metabolism, and diagnostic and therapeutic agents for the treatment of iron overload diseases and iron deficiency diseases.
One aspect of the invention is a method of treating an iron overload disease by administering to a patient an HFE polypeptide having the sequence of SEQ ID NO:1,
RLLRSHSLHYLFMGASEQDLGLSLFEALGYVDDQLFVFYDHESRRVEPRTPWVSSRISSQMWLQLSQSLKGWDHMFTVDFWTIMENHNHSKESHTLQVILGCEMQEDNSTEGYWKYGYDGQDHLEFCPDTLDWRAAEPRAWPTKLEWERHKIRARQNRAYLERDCPAQLQQLLELGRGVLDQQVPPLVKVTHHVTSSVTTLRCRALNYYPQNITMKWLKDKQPMDAKEFEPKDVLPNGDGTYQGWITLAVPPGEEQRYTCQVEHPGLDQPLIVIWE,
wherein the HFE polypeptide is provided in a complex with full length, wild type human xcex22m.
A further aspect of the invention is a composition of an HFE polypeptide having the amino acid sequence of SEQ ID NO:1,
RLLRSHSLHYLFMGASEQDLGLSLFEALGYVDDQLFVFYDHESRRVEPRTPWVSSRISSQMWLQLSQSLKGWDHMFTVDFWTIMENHNHSKESHTLQVILGCEMQEDNSTEGYWKYGYDGQDHLEFCPDTLDWRAAEPRAWPTKLEWERHKIRARQNRAYLERDCPAQLQQLLELGRGVLDQQVPPLVKVTHHVTSSVTTLRCRALNYYPQNITMKWLKDKQPMDAKEFEPKDVLPNGDGTYQGWITLAVPPGEEQRYTCQVEHPGLDQPLIVIWE,
wherein the HFE polypeptide is provided in a complex with full length, wild type human xcex22m.
A further aspect of the invention is a method of treating an iron deficiency disease by administering to a patient an HFE polypeptide, i.e., H63D-HFE mutant, having the sequence of SEQ ID NO:2,
RLLRSHSLHYLFMGASEQDLGLSLFEALGYVDDQLFVFYDDESRRVEPRTPWVSSRISSQMWLQLSQSLKGWDHMFTVDFWTIMENHNHSKESHTLQVILGCEMQEDNSTEGYWKYGYDGQDHLEFCPDTLDWRAAEPRAWPTKLEWERHKIRARQNRAYLERDCPAQLQQLLELGRGVLDQQVPPLVKVTHHVTSSVTTLRCRALNYYPQNITMKWLKDKQPMDAKEFEPKDVLPNGDGTYQGWITLAVPPGEEQRYTCQVEHPGLDQPLIVIWE,
wherein the HFE polypeptide is provided in a complex with full length, wild type human xcex22m.
A further aspect of the invention is a composition of an HFE polypeptide, i.e., H63D-HFE mutant, having the amino acid sequence of SEQ ID NO:2,
RLLRSHSLHYLFMGASEQDLGLSLFEALGYVDDQLFVFYDDESRRVEPRTPWVSSRISSQMWLQLSQSLKGWDHMFTVDFWTIMENHNHSKESHTLQVILGCEMQEDNSTEGYWKYGYDGQDHLEFCPDTLDWRAAEPRAWPTKLEWERHKIRARQNRAYLERDCPAQLQQLLELGRGVLDQQVPPLVKVTHHVTSSVTTLRCRALNYYPQNITMKWLKDKQPMDAKEFEPKDVLPNGDGTYQGWITLAVPPGEEQRYTCQVEHPGLDQPLIVIWE,
wherein the HFE polypeptide is provided in a complex with full length, wild type human xcex22m.
A further aspect of the invention is a method of treating an iron deficiency disease by administering to a patient an HFE polypeptide, i.e., H111A/H145A-HFE mutant, having having the sequence of SEQ ID NO:3,
RLLRSHSLHYLFMGASEQDLGLSLFEALGYVDDQLFVFYDHESRRVEPRTPWVSSRISSQMWLQLSQSLKGWDHMFTVDFWTIMENHNASKESHTLQVILGCEMQEDNSTEGYWKYGYDGQDALEFCPDTLDWRAAEPRAWPTKLEWERHKIRARQNRAYLERDCPAQLQQLLELGRGVLDQQVPPLVKVTHHVTSSVTTLRCRALNYYPQNITMKWLKDKQPMDAKEFEPKDVLPNGDGTYQGWITLAVPPGEEQRYTCQVEHPGLDQPLIVIWE,
wherein the HFE polypeptide is provided in a complex with full length, wild type human xcex22m.
A further aspect of the invention is a composition of an HFE polypeptide, i.e., H111A/H145A-HFE mutant, having the amino acid sequence of SEQ ID NO:3,
RLLRSHSLHYLFMGASEQDLGLSLFEALGYVDDQLFVFYDHESRRVEPRTPWVSSRISSQMWLQLSQSLKGWDHMFTVDFWTIMENHNASKESHTLQVILGCEMQEDNSTEGYWKYGYDGQDALEFCPDTLDWRAAEPRAWPTKLEWERHKIRARQNRAYLERDCPAQLQQLLELGRGVLDQQVPPLVKVTHHVTSSVTTLRCRALNYYPQNITMKWLKDKQPMDAKEFEPKDVLPNGDGTYQGWITLAVPPGEEQRYTCQVEHPGLDQPLIVIWE,
wherein the HFE polypeptide is provided in a complex with full length, wild type human xcex22m.